(a) Field
The subject matter disclosed generally relates to compositions and methods for the treatment of respiratory conditions, and more particularly to compositions and methods for treating pulmonary hypertension, acute chest syndrome and other symptoms of sickle-cell diseases, as well as other respiratory conditions, comprising an amino acid ester compound and a inhalable carrier.
(b) Related Prior Art
Nitric oxide relaxes pulmonary vessels, in particular when they are constricted by various disorders. Nitric oxide also relaxes airway smooth muscle and inhalation of exogenous nitric oxide attenuates airway constriction in the response to various agents in laboratory animals and humans. Thus, for instance EP 560 928, U.S. Pat. No. 5,485,827, U.S. Pat. No. 5,873,359 and WO 92/10228 disclose the use of nitric oxide for treating bronchoconstriction and pulmonary vasoconstriction.
NO inhalation (INO) is an efficient therapy in patients respiratory conditions such as pulmonary hypertension and acute chest syndrome. However, around ⅓ of the patients are hypo- or non-responders to INO. In addition thereto, worsening of the pulmonary hypertension and of the oxygenation have been observed during attempts to withdraw INO, which is termed rebound response. Life-threatening hemodynamic instability and deaths by discontinuing inhalation of nitric oxide have also been reported. Stepwise lowering of the NO dose will prolong the NO therapy but may still not eliminate the rebound response.
Sickle-cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Acute pain crisis, acute chest syndrome (ACS), and secondary pulmonary hypertension are common complications of sickle-cell disease. Pulmonary hypertension has now been identified as a major cause of death in adults with sickle cell disease. Common treatments for sickle-cell disease in children and young adults are continuous antibiotic therapy, use of hydroxyurea to lessen the acute chest syndrome, both of which have major side effects. Sickle cell is characterized by acute chest syndrome wherein deformed blood cells cannot pass through the constricted capillaries in the lungs and blockages occur causing severe pain and even death. These episodes were thought to be rare, but recent research shows that small episodes are an almost constant problem in the affected individuals.
Current research has also shown a direct link to the lack of nitric oxide and vasodilation in this acute state. Scavenging of nitric oxide by hemoglobin and disruption of nitric oxide release function contribute to the acute state in sickle-cell disease. Inhaled nitric oxide (NO) has been proposed as a possible therapy for both primary and secondary pulmonary hypertension. Furthermore, a number of recent studies have suggested that NO may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle-cell disease. In addition, chronic exchange transfusion therapy may reduce the progression and/or severity of pulmonary hypertension in these patients. However nitric oxide gas administration is cumbersome, costly and can only be done in intensive care units with vigilance since over administration can be toxic. Also, a disadvantage of nitric oxide gas is that it has only a small penetration into tissue as it is reactive and has very short half life. A commonly used alternative is the use of nitroglycerin. However, there are several drawbacks to the manufacture, storage and use of nitroglycerin. Nitroglycerin is an explosive compound that is difficult to produce and stabilize. It is inherently unstable over the long term resulting in a maximum shelf life of a product containing of about six months.
Nitroprusside is another alternative compound that can be used to release NO to effect peripheral vasodilation in arterioles and venules, but the compound has the disadvantage of decomposing into very toxic cyanide ions.
A major drawback to the long term usage of nitroglycerin for the treatment of diseases is that the metabolic pathway for the liberation of nitric oxide from nitroglycerin occurs in the mitochondria, utilizing the aldehyde dehydrogenase 2 enzyme. The liberation of large amounts of nitric oxide within the mitochondria from the use of nitroglycerin proves to be toxic to the mitochondria over time and eventually causes extensive metabolic disruption. Also, certain classes of patient suffering from nitric oxide deficiencies, mainly of Asian descent, have been shown to carry a recessive allele of the gene producing aldehyde dehydrogenase 2 which renders them non-responsive to the use of nitroglycerin. Therefore, there is a need for alternative compounds to nitroglycerin and nitroprusside.
It is thus desirable to provide a composition and method for the treatment of pulmonary diseases which contains an alternative compound than gaseous NO, nitroglycerin or nitroprusside, and does not require any special operational procedures other than the inhalation of a composition.
It is also desirable to provide a composition and method for the treatment of pulmonary diseases which contains an alternative compound than gaseous NO, nitroglycerin or nitroprusside, and that lessens the rebound response when discontinuing inhalation of nitric oxide.
It is also desirable to provide a composition that can alter or at least improve the nitric oxide levels in the lungs of sickle-cell disease and acute chest syndrome sufferers while providing longer lasting prophylaxis than the few minutes afforded by nitric oxide gas infusion.
It is thus desirable to provide a method for the treatment of sickle-cell disease and/or acute chest syndrome which contains an alternative compound than gaseous NO or nitroglycerin, and does not require any special operational procedures other than the inhalation of a composition.